1. Introduction
The following description in this Background section includes information that may be useful in understanding the present invention. It is not an admission that any such information is prior art, or relevant, to the presently claimed inventions, or that any publication specifically or implicitly referenced is prior art. In this specification, a number of documents including patent applications are cited. The disclosures of these documents, while not considered relevant for the patentability of this invention, are hereby incorporated by reference in their entirety. More specifically, all referenced documents are incorporated by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference.
2. Background
In the United States, with an estimated 6.8 percent of the population aged 12 or older classified as having alcohol dependence or abuse (1), alcohol remains the most prevalent abused substance in the USA (1). Few pharmacotherapies for alcohol abuse are currently available, and those that exist have shown only limited efficacy, poor patient compliance, etc. (2-4). Thus, the development of more efficacious and safe alcohol abuse/dependence medications is a significant unmet medical need (5).
Carbenoxolone (3β-hydroxy-11-oxoolean-12-en-30-oic acid 3-hemisuccinate) is the hemisuccinate derivative of 18β-glycyrrhetinic acid (GA), a metabolite of the natural product glycyrrhizin present in licorice (6). Carbenoxolone has long been used for the treatment of gastritis and peptic ulcers (7). Subsequent studies focused on elucidating the mechanism of action of carbenoxolone have highlighted that carbenoxolone modulates glucocorticoid metabolism in target tissues by inhibiting 11β-hydroxysteroid dehydrogenases (11β-HSD) (8) and, at potencies several orders of magnitude higher, gap junction communication (9). 11β-HSD interconverts 11-hydroxi (active) glucocorticoids (cortisol in humans and corticosterone in rodents) and inert 11-keto glucocorticoids (cortisone in humans and 11β-dehydrocorticosterone in rodents) in target cells, thus acting as pre-receptor (8). In particular, there are at least two known isozymes of 11β-HSD: type 1 (11β-HSD1) and type 2 (11β-HSD2). In vivo, 11β-HSD1 catalyses the regeneration of cortisol in humans and corticosterone in rodents from cortisone in humans and 11β-dehydrocorticosterone in rodents using the cofactor NADPH, while 11β-HSD2 catalyses the reverse reaction using the cofactor NAD+ (8). An 11β-HSD3 isozyme has also been described, whose physiological function remains unclear (10). Carbenoxolone inhibits 11β-HSD isozymes in an isozyme non-selective manner (11).
Glucocorticoids are key in the regulation of stress responses, carbohydrate, lipid and protein metabolism and turnover, blood pressure, cell growth and differentiation, neuronal and immune functions, and alcohol and drug abuse (12-14). A complex regulatory network is involved in the regulation of glucocorticoid actions, with 11β-HSD enzymes regulating intracellular glucocorticoid levels and receptor access (8).
Impaired glucocorticoid regulation has been implicated in the pathogenesis of several diseases and, thus, modulation of intracellular glucocorticoid levels is a potential therapeutic strategy to treat glucocorticoid-dependent diseases. 11β-HSD1 is expressed primarily in the liver, brain, and adipose tissue (8). Inhibition of 11β-HSD1 reduces the intracellular availability of active glucocorticoids such as cortisol in humans and corticosterone in rodents (8). In both humans and rodents, elevated 11β-HSD1 activity has been associated with metabolic disorders (9, 15-18) and age-related cognitive impairments (19, 20). 11β-HSD2 is expressed in classic mineralocorticoid target tissues including the kidney, colon, sweat and salivary glands (21). 11β-HSD2 is also expressed in the placenta, where it protects the fetus from excess glucocorticoids (22-24), as well as in inflamed tissue and several tumors and cancer cell lines (21). Inhibition of 11β-HSD2 is responsible for the adverse effects of enhanced renal sodium retention and elevated blood pressure in patients with mutations of HSD11B2 (25) and in individuals ingesting high amounts of licorice, which contains the non-selective 11β-HSD inhibiting triterpenoid glycyrrhetinic acid (GA) and in some patients treated with the non-selective 11β-HSD inhibitor carbenoxolone (26-28). However, recent evidence indicates potential beneficial effects of 11β-HSD2 inhibition in chronic inflammatory diseases of the colon and on colon cancer cell proliferation. In particular, 11β-HSD2 regulates the activity of several enzymes involved in inflammatory and other responses such as NfKB (29) and COX (30). Furthermore, a recent clinical study suggested that 11β-HSD2 inhibition promotes potassium excretion and prevents hyperkalemia in chronic hemodialysis patients (31). Thus, 11β-HSD2 inhibition may also be therapeutically useful.
It is also understood that alcohol use disrupts glucocorticoid regulation in rodents (32, 33) as well as humans (34-37). Regardless of what is known about the functional consequences of such a dysregulation, there is a significant lack of understanding regarding this particular regulation cascade. However, it has been reported that glucocorticoid activation by alcohol is associated with escalation of alcohol intake in dependent rats and alcohol-seeking and drinking during protracted abstinence (13). In that study, mifepristone (RU38486), a glucocorticoid receptor antagonist with progesterone partial agonist activity, was used to antagonize glucocorticoid activation and the blocking of activation by systemic glucocorticoid receptor (GR) antagonism blocked escalated alcohol drinking and compulsive response for alcohol (35). In still another study, in humans, high adrenal sensitivity, as expressed by a high cortisol to corticotropin ratio at rest (neutral, relaxed conditions), was found to correlate with greater susceptibility of relapse to heavy drinking (37).
Only a limited number of drugs exist with clinical efficacy for alcohol abuse (5). Expansion of available therapeutic options is needed to improve treatment success at different stages of disease progression and, optimally, to bring about individualized therapies based on patient genetic makeup and disease stage (5, 38). Given that there is an ongoing need for effective medications for treating and ameliorating substance use disorder, abuse, and/or dependence for substances such as alcohol, this invention provides a new solution for treating alcohol substance abuse through the novel discovery that compounds capable of inhibiting 11β-hydroxysteroid dehydrogenases (11β-HSD) can be used to ameliorate excessive alcohol intake.
Thus, as described below, methods and compositions are provided for reducing dependence and otherwise excessive intake of alcohol in mammals including humans.